Malaria poses an enormous health problem worldwide, causing approximately 200 million new cases annually with disease spectrum ranging from asymptomatic parasitemia to severe malaria and death. Peripheral blood monocytes are a dynamic cell population that are rapidly recruited to sites of infection and play a key role at the interface between innate and adaptive immunity. While activation of the innate immune response is necessary to control blood stage infection, excessive activation of monocytes and other innate immune cells contributes to malaria pathogenesis. Studies have demonstrated memory phenotypes in innate immunity. Upon interaction with pathogens, innate immune cells undergo epigenetic changes that result in cellular reprogramming and altered responses to subsequent challenge. Depending on the dose and type of initial stimulus, epigenetic reprogramming can lead to ?training? with increased pro-inflammatory cytokine responses, or to ?tolerance? with diminished pro-inflammatory cytokine responses to a subsequent stimulus. In our preliminary data, we found that monocytes from Kenyan children experiencing acute uncomplicated malaria and upon recovery 6 weeks later produced high levels of pro-inflammatory cytokines to TLR agonists, a phenotype consistent with ?trained? innate immunity. We hypothesize that malaria causes epigenetic changes in monocyte precursors that modify specific gene signaling pathways important to innate immune functions. Low parasite loads in uncomplicated malaria lead to innate immune training whereas high parasite loads in severe malaria lead to innate immune paralysis (tolerance). Using previously collected samples from our longitudinal studies of children with acute uncomplicated malaria and samples from our ongoing severe malaria study in Western Kenya, we will decipher the gene pathways important in monocyte function utilizing DNA methylation arrays combined with RNA-Seq examination of gene expression. These epigenetic and transcriptomic changes will be coupled with ex vivo monocyte challenge to determine immune memory phenotypes (trained vs. tolerance) and persistence over time in Kenyan children. This research is a joint effort of investigators with experience and training in malaria biology and epidemiology, clinical medicine, monocyte immunology, genomic technology, and bioinformatics. Results from these high-yield innovative studies will address fundamental gaps in our understanding of the mechanisms of innate immunity to malaria and identify specific host pathways that may become targets of adjunct therapies to antimalarial drug treatment of uncomplicated and severe malaria.